Pharmaceutical compositions comprising a benzofuran derivative and their use for the treatment of attention deficit/hyperactivity disorder

ABSTRACT

The compound of formula (I): or a pharmaceutically acceptable salt thereof, especially the mesylate salt, is of use in a method for the treatment and/or prevention of attention-deficit/hyperactivity disorder (ADHD).

This invention relates to the use of a particular heteroaromaticcompound. More particularly, the invention is concerned with the use ofa (1,2,3,6-tetrahydropyridin-1-yl)methyl substituted benzofuranderivative which is a selective antagonist of the dopamine D₄ receptorsubtype within the brain and is therefore of benefit in the treatmentand/or prevention of attention-deficit/hyperactivity disorder (ADHD).

ADHD is a condition characterised by inattentive, impulsive hyperactivebehaviour, and affects some 6% of school age boys in the USA. Althoughprimarily affecting children, in some cases the symptoms persist intoadulthood. Several recent studies have implicated the dopamine D₄receptor in the etiology of ADHD (see, for example, Zhang et al.,Neuropsychopharmacology, 2001, 25, 624632, and references therein).

EP-A-1177792 relates to the use of a dopamine D₄ receptor ligand in thetreatment or prevention of a novelty-seeking disorder, includingattention deficit disorder with hyperactivity disorder. There is in thatpublication, however, no disclosure nor any suggestion of employing thespecific benzofuran derivative of formula I as depicted below, or apharmaceutically acceptable salt thereof, in the therapy of ADHD.

WO 02/072029, published on 19 Sep. 2002, describes and claims a methodof inhibiting motor hyperactivity in a mammal exhibiting the symptoms ofADHD, which comprises administering thereto a compound selected from alist of known dopamine D₄ receptor antagonists. That list does not,however, include the compound of formula I as depicted below or apharmaceutically acceptable salt thereof.

U.S. Pat. No. 5,665,722 discloses a class of substituted benzofuranderivatives which are selective dopamine D₄ receptor antagonists andwhich are said to be useful in the treatment of schizophrenia.

According to the present invention, there is provided a method oftreating or preventing ADHD comprising administering to a subject inneed thereof a therapeutically-effective amount of the compound offormula I:

or a pharmaceutically acceptable salt thereof.

Many of the known dopamine D₄ receptor antagonists, e.g. L-745,870 (cf.WO 02/072029), incorporate an indole or aza-indole ring system intotheir molecular structure, and are accordingly susceptible to beingmetabolised by a retro-Mannich mechanism, leading to the formation ofpotentially toxic by-products, e.g. covalent glutathione adducts. Themolecular structure of the benzofuran derivative of formula I above,meanwhile, is devoid of an indole or aza-indole ring system; use of thiscompound in the therapy of ADHD is therefore advantageous, in that thereis consequently no possibility of metabolism by a retro-Mannich route.

In one embodiment of the present invention, the subject is a human male.In this embodiment, the subject is typically a human male aged 5-18years, preferably aged 12-18 years.

The method of treatment according to the invention typically comprisesadministering to the subject a tablet containing from 1 to 100 mg of thecompound of formula I or pharmaceutically acceptable salt thereof once,twice, three times or four times a day. Preferably, the tablet containsfrom 2 to 50 mg, more preferably from 5 to 25 mg, of the compound offormula I or pharmaceutically acceptable salt thereof, and isadministered once or twice a day. In a particular embodiment, a tabletcontaining 15 mg of the compound of formula I or pharmaceuticallyacceptable salt thereof is administered once a day.

The method of treatment according to the invention may be used fortreatment of ADHD which is of the combined type, or which is of thepredominantly inattentive type, or which is of the predominantlyhyperactive-impulsive type.

There is further disclosed the use of the compound of formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for treatment or prevention of ADHD.

For use in medicine, the salts of the compound of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compound of use in the invention or of itspharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compound of use in this invention include acid additionsalts which may, for example, be formed by mixing a solution of thecompound of use in the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid,citric acid, tartaric acid, methanesulphonic acid, carbonic acid orphosphoric acid. Examples of preferred salts include themethanesulphonate (mesylate) salt.

The medicaments relevant to the invention are typically pharmaceuticalcompositions comprising the compound of formula I, or pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier. Preferably these compositions are in unit dosageforms such as tablets, pills, capsules, powders, granules, sterileparenteral solutions or suspensions, metered aerosol or liquid sprays,drops, ampoules, auto-injector devices or suppositories; for oral,parenteral, intranasal, sublingual or rectal administration, or foradministration by inhalation or insufflation. Alternatively, thecompositions may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of the compound of formulaI, or a non-toxic pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of use in the present invention.Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 2,5, 10, 15, 25, 50 or 100 mg, of the active ingredient. The tablets orpills can be coated or otherwise compounded to provide a dosage formaffording the advantage of prolonged action. For example, the tablet orpill can comprise an inner dosage and an outer dosage component, thelatter being in the form of an envelope over the former. The twocomponents can be separated by an enteric layer which serves to resistdisintegration in the stomach and permits the inner component to passintact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the compositions relevant to the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of ADHD, a suitable dosage level is about 0.01 to 250mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

In order to alleviate the symptoms of ADHD without causing sedation orextrapyramidal side-effects, the dosage level of the compound of formulaI may be selected such that the dose administered is effective insubstantially completely blocking the dopamine D₄ receptor subtype inhuman brain whilst displaying no or negligible dopamine D₂ receptorsubtype occupancy. A suitable dosage level in this regard is about 0.001to 5.0 mg/kg per day, more particularly about 0.005 to 1.0 mg/kg perday, and especially about 0.01 to 0.5 mg/kg per day.

EXAMPLE 1

Use of the Compound of Formula I for Treatment of ADHD

The mesylate salt of the compound of formula I is prepared as describedin Example 1 of GB 2,306,471. Tablets comprising 15 mg of this activeingredient are prepared by conventional means and a single tablet isadministered once a day to a subject suffering from, or prone to, ADHD.

1-4. (canceled)
 5. A method for the treatment ofattention-deficit/hyperactivity disorder comprising administering to asubject in need thereof a therapeutically effective amount of thecompound of formula I:

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5wherein the mesylate salt of the compound of formula I is administeredto the subject.
 7. The method of claim 5 wherein the subject is a humanmale.
 8. The method of claim 7 wherein the subject is a human male aged5-18 years.
 9. The method of claim 5 wherein theattention-deficit/hyperactivity disorder is of the combined type. 10.The method of claim 5 wherein the attention-deficit/hyperactivitydisorder is of the predominantly inattentive type.
 11. The method ofclaim 5 wherein the attention-deficit/hyperactivity disorder is of thepredominantly hyperactive-impulse type.
 12. A method for the preventionof attention-deficit/hyperactivity disorder comprising administering toa subject in need thereof a therapeutically effective amount of thecompound of formula I:

or a pharmaceutically acceptable salt thereof.
 13. The method of claim12 wherein the mesylate salt of the compound of formula I isadministered to the subject.
 14. The method of claim 12 wherein thesubject is a human male.
 15. The method of claim 14 wherein the subjectis a human male aged 5-18 years.
 16. The method of claim 12 wherein theattention-deficit/hyperactivity disorder is of the combined type. 17.The method of claim 12 wherein the attention-deficit/hyperactivitydisorder is of the predominantly inattentive type.
 18. The method ofclaim 12 wherein the attention-deficit/hyperactivity disorder is of thepredominantly hyperactive-impulse type.